The pancreatic ?-cells are responsible for producing insulin and maintaining glucose homeostasis. A loss of ?-cells or their inability to compensate for insulin resistance is the major cause for type I and type 2 diabetes, respectively. Increasing ?-cell mass or generating optimally functional islets in vitro for transplantation could potentially improve or cure diabetic conditions. Thus, efforts have been focused on improving ?-cell mass by understanding and manipulating the mechanisms involved in their differentiation, proliferation and regeneration. PTEN is a lipid phosphatase that antagonizes the function of the PI3K signaling pathway. Targeted deletion of Pten in insulin producing cells led to a significant increase in total islet mass. This study suggests that ?-cell regeneration may be under mitogenic regulation and that PTEN may be regulating ?-cell regeneration in a paracrine fashion. To understand the biology underlying ?-cell regeneration, we performed immunohistological (IHC) analysis in a ?-cell injury and non-injury model. We demonstrated that the proliferating cells are most likely originating from previous-existing ?-cells under normal physiological conditions, but seem to induce proliferation of surrounding non-?-cells in the streptozotocin (STZ)-treated mice. To further confirm this observation, we used a reporter mouse model, Ptenlox/lox;Rosa26lacZ;Rip-Cre+, to determine the origin of the proliferating cells. Our preliminary analysis showed that the effect of PTEN on ?-cellproliferation may be intrinsic and that ?-cells themselves are contributing to ?-cell regeneration. However, when STZ was administered to these mice, the loss of PTEN in ?-cell produced a paracrine effect to induce a proliferation of surrounding non-beta-cells and non-islet cells. Further IHC analysis suggests that this loss of PTEN in ?-cells lead to the expansion of surrounding mesenchyme in these STZ-treated mice. Together, our present studies suggest that mitogenic signaling, such as those regulated by PTEN, may regulate ?-cell proliferation and regeneration under physiological conditions in a cell intrinsic manner, but may induce a paracrine effect during ?-cell injury.